Effect of Inhaled Colistin on the Treatment of Ventilator-Associated Pneumonia due to Multi-drug Resistant Acinetobacter.

Background
Ventilator-Associated Pneumonia (VAP) is a hospital pneumonia that is considered in patients on mechanical ventilation for at least 48 hours with symptoms of new lower respiratory tract infections being reported in them. The present study reviews the effect of adding inhaled colistin in the treatment of ventilator-induced pulmonary infections in Intensive Care Unit (ICU) patients.


Materials and Methods
In this single blind clinical trial, patients admitted to the ICU with diagnosis of pulmonary infections caused by ventilator were investigated. In the treatment group, patients received 150 mg of colistin plus 1,000,000 units inhaled colistin every eight hours and in the control group only 300 mg of colistin every eight hours intravenously was given. Patients were followed up in terms of clinical findings for seven days after the initial diagnosis of infection.


Results
The results of this study showed that administration of inhaled colistin in patients admitted in ICU significantly improved culture indices, leukocyte, white blood cell count, chest X-ray, chest secretion, CPIS score and saccharification (SpO2) on the third and seventh days after treatment compared to the first day.


Conclusion
Considering the positive effect of adding inhaled colistin to the treatment of patients admitted to ICU with pulmonary infections caused by ventilator with multi-drug resistant Acinetobacter, the use of combination drug therapy is recommended.


INTRODUCTION
A large number of studies have shown that Ventilator-Associated Pneumonia (VAP) is the most common nosocomial infection and one of the most frequent complications among patients admitted to hospitals and particularly for Intensive Care Unit (ICU) patients (1)(2)(3)(4)(5). As a result of recent researches, intubation with mechanical ventilation raises the risk of pneumonia by 6 to 20 fold among patients and is associated with 20-40 percent crude mortality rates (6,7). Pneumonia caused by VAP is the most common fatal infection which demands for prescription of parenteral antibiotics (7,8). About 20% of hospitalacquired pneumonia is due to using mechanical ventilation (9). The rate of mortality for nosocomial pneumonia ranges from 38 to 70%, and even higher rates for Multidrug Resistant Gram-Negative (MDR-GN) organisms (10).
Recent studies indicate that the incidence of lower respiratory tract infection due to MDR pathogens and gram-negative bacilli such as Acinetobacter baumannii has been increasing (6,7). Therefore, according to the 2005 Because of potent bactericidal action of colistin, low incidence of resistances, and excellent activity against gram-negative bacilli, even MDR strains, colistin was used as a polymycin antibiotic agent in the 1960s and 1980s (11).
Colistin does not increase cross-resistance of gramnegative bacilli and its' mechanism of action makes it less susceptible to bacterial resistance mechanisms (12,13).
Over 20 years, inhaled colistin has been used successfully to prevent and cure pulmonary infections in cystic fibrosis patients (14). There are only few studies available assessing the effectiveness of inhaled colistin for the treatment of nosocomial pneumonia and particularly VAP (15,16).
Inhaled colistin has been used for both early and chronic infection in Europe and in the United States. The evidence from large controlled trials would support its use (17)(18)(19)(20)(21)(22)(23). But there are limited and conflicting data on the efficacy and adverse effects regarding inhaled colistin in the treatment of VAP in patients (24)(25)(26). This study compared the efficacy and safety rate of administering inhalation and intravenous colistin versus only intravenous colistin in patients with MDR-GN VAP. On the first, third and seventh days after intervention, the patients were sampled and followed in terms of clinical and laboratory findings such as fever (>38 0 C), number of leukocytosis, plasma creatinine, plasma urea, SpO 2 , FiO 2 , blood pressure, heart rate, body temperature, and number of breaths per minute. Also on the seventh day, re-cultivation was carried out and in terms of changes in the nature of the patient's Clinical Pulmonary Infection Score (CPIS) score was checked by the doctor using the same procedure.

CPIS test Characteristic
The CPIS was calculated as an appropriate tool to

DISCUSSION
This study demonstrated that patients with MDR-GN pneumonia treated with both inhaled colistin and IV colistin compared to patients who received IV colistin had a more favorable outcome. The results of the study showed that during 7 days after treatment, inhaled colistin was well tolerated and the speed of recovery of patients in treatment group was higher than the control group which was in the same line with Korbila et al. (26). Also the mortality rate in both groups was approximately equal.
It should be mentioned that the studied patients in both groups were matched in terms of age, gender and weight in the two groups. A. baumannii (32). This polypeptide antibiotic is effective against most Gram-negative bacilli (33). Due to the absence of effective alternative cure, IV colistin has been used in patients with VAP caused by MDR-GN pathogens as salvage treatment (33,34).
Results of studies on the effect of direct delivery of antibiotics such as colistin were clinically beneficial to patients by increasing topical drug levels (35)(36)(37). Due to the increase of morbidity and mortality rate in patients with MDR-GN infections, it is important to determine if inhaled colistin had better healing results (25). Aside from the intravenous administration of colistin, it can be used as inhaled colistin whose effectiveness has been proven (18).
Some studies reported that combination therapy (inhaled colistin as adjunctive therapy to IV colistin therapy) had  (44,45); but renal dysfunction is the most frequent reported adverse effect in the critically ill patients in the ICU setting (46). In other studies, the incidences of nephrotoxicity were reported as the main limiting factor for colistin usage in adults (24,38,47). In the current study a total of 5 patients in treatment group and 7 patients in control group experienced nephrotoxicity after treatment. Although the incidence of nephrotoxicity was higher in control group but it was not statistically different.
The current study had some limitations that should be mentioned. It was not possible to control the particle size of real inhaled colistin which was administered via conventional nebulizers and as a result the exact amount of drug delivered to the lungs could not be exactly determined (48,49). We also should note that this was a retrospective study and only single-center site. This comparative evidence is only available to make a decision between IV antibiotics and inhaled colistin treatment to determine usefulness of inhaled colistin for VAP at that time.

CONCLUSION
The results showed that receiving 150 mg colistin in addition to 1,000,000 units of inhaled colistin (inhaled-